The availability of potent new immunosuppressive drugs has led to a dramatic decrease in the incidence of early episodes of acute rejection in kidney transplant recipients. However, toxicities of currently available immunosuppressants ironically may influence long-term allograft and patient outcomes negatively by causing renal dysfunction and promoting cardiovascular disease. This review summarizes recent clinical experience with immunosuppression protocols designed to minimize these long-term toxicities by reducing or eliminating doses of calcineurin inhibitors or corticosteroids. Long-term follow-up of patients enrolled in such studies is needed to establish the durability of encouraging preliminary results.